title: Structure and mechanism of metallocarboxypeptidases.
abstract: Metallocarboxpeptidases cleave C-terminal residues from peptide substrates and participate in a wide range of physiological processes, but they also contribute to human pathology. On the basis of structural information, we can distinguish between two groups of such metallopeptidases: cowrins and funnelins. Cowrins comprise protozoan, prokaryotic, and mammalian enzymes related to both neurolysin and angiotensin-converting enzyme and their catalytic domains contain 500-700 residues. They are ellipsoidal and traversed horizontally by a long, deep, narrow active-site cleft, in which the C-terminal residues are cut from oligopeptides and unstructured protein tails. The consensus cowrin structure contains a common core of 17 helices and a three-stranded beta-sheet, which participates in substrate binding. This protease family is characterized by a set of spatially conserved amino acids involved in catalysis, HEXXH+EXXS/G+H+Y/R+Y. Funnelins comprise structural relatives of the archetypal bovine carboxypeptidase A1 and feature mammalian, insect and bacterial proteins with strict carboxypeptidase activity. Their approximately 300-residue catalytic domains evince a consensus central eight-stranded beta-sheet flanked on either side by a total of eight helices. They also contain a characteristic set of conserved residues, HXXE+R+NR+H+Y+E, and their active-site clefts are rather shallow and lie at the bottom of a funnel-like cavity. Therefore, these enzymes act on a large variety of well-folded proteins. In both cowrins and funnelins, substrate hydrolysis follows a common general base/acid mechanism. A metal-bound solvent molecule ultimately performs the attack on the scissile peptide bond with the assistance of a strictly conserved glutamate residue.
authors.affiliation: Molecular Biology Institute of Barcelona, CSIC, Barcelona, Spain. xgrcri@ibmb.csic.es
authors.forename: F Xavier
authors.initials: FX
authors.lastname: Gomis-Rüth
mesh_terms: D000818:Animals; D055162:Biocatalysis; D002268:Carboxypeptidases / Q000737:chemistry* / Q000378:metabolism* / Q000502:physiology; D020134:Catalytic Domain / Q000502:physiology; D006801:Humans; D045726:Metalloproteases / Q000737:chemistry* / Q000378:metabolism* / Q000502:physiology; D015032:Zinc / Q000737:chemistry* / Q000502:physiology*
chemical_list: D002268:Carboxypeptidases; D045726:Metalloproteases; D015032:Zinc